ABSTRACT The morbidity and mortality of diabetes mellitus occurs largely from its major complications, which include diabetic kidney disease (DKD), diabetic neuropathy (DN) and retinopathy (DR). Although extensive data exist on disease mechanisms in experimental models, the pathogenesis of human diabetic complications remains unclear except that hyperglycemia is a major risk factor for all complications. Our studies have led to an emerging paradigm that while complication prone tissues share similar elements, they are intrinsically distinct in their response to the diabetic state. Thus, the biological effects of the metabolic abnormalities depend on the cellular microenvironment of the target tissue. Moreover, alterations in lipid profiles have emerged from our studies as a potential basis for both biomarkers of complication progression and for mechanistic understanding of the tissue-specific metabolic alterations that lead to these complications. These observations form the basis of the competing renewal that seeks to broaden our understanding of the unique and shared molecular basis of diabetic complications. Our preliminary data demonstrate that changes in renal lipid-related gene expression and plasma lipids predict long-term progression in human DKD after adjustment for HbA1C. Additionally, while diabetic mouse kidney exhibits increased fatty acid oxidation (FAO), the diabetic nerve and retina demonstrate markedly lower FAO, suggesting tissue specific changes in lipid utilization and metabolism. These findings led to our hypothesis that complication prone tissues demonstrate unique alterations in lipid metabolism that cause dysfunction. Our plan is to: 1) identify lipid biomarkers for the critical responses that lead to the onset, progression and response to therapy of DKD, DN and DR; 2) discover the essential cellular lipid metabolism responses that lead to DKD, DN and DR; and 3) from these responses, identify those that are amenable to novel therapies. Our strategy relies on information-rich sequential and reciprocal genetic, transcriptomic, proteomic and lipidomic comparisons between humans with DKD, DN and DR and the best available murine models of these complications. These studies will be pivotal in identifying novel mechanisms and therapeutic targets in diabetic complications.